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Updated: May 19, 2026
Purification of Endogenous Drosophila Transient Receptor Potential Channels
Published on: December 28, 2021
Drosophila TRPML is required for TORC1 activation
Ching-On Wong1, Ruoxia Li, Craig Montell
1Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA.
Abstract:
Loss-of-function mutations in TRPML1 (transient receptor potential mucolipin 1) cause the lysosomal storage disorder, mucolipidosis type IV (MLIV). Here, we report that flies lacking the TRPML1 homolog displayed incomplete autophagy and reduced viability during the pupal period--a phase when animals rely on autophagy for nutrients. We show that TRPML was required for fusion of amphisomes with lysosomes, and its absence led to accumulation of vesicles of significantly larger volume and higher luminal Ca(2+). We also found that trpml(1) mutant cells showed decreased TORC1 (target of rapamycin complex 1) signaling and a concomitant upregulation of autophagy induction. Both of these defects in the mutants were reversed by genetically activating TORC1 or by feeding the larvae a high-protein diet. The high-protein diet also reduced the pupal lethality and the increased volume of acidic vesicles. Conversely, further inhibition of TORC1 activity by rapamycin exacerbated the mutant phenotypes. Finally, TORC1 exerted reciprocal control on TRPML function. A high-protein diet caused cortical localization of TRPML, and this effect was blocked by rapamycin. Our findings delineate the interrelationship between the TRPML and TORC1 pathways and raise the intriguing possibility that a high-protein diet might reduce the severity of MLIV.
Insights
Loss-of-function mutations in TRPML1 cause mucolipidosis type IV (MLIV). In flies, TRPML1 is crucial for autophagy and lysosomal fusion; a high-protein diet rescues MLIV-like defects by modulating TORC1 signaling.
Area of Science:
- Cell Biology
- Genetics
- Physiology
Background:
- Loss-of-function mutations in TRPML1 (transient receptor potential mucolipin 1) are the cause of mucolipidosis type IV (MLIV), a lysosomal storage disorder.
- TRPML1 plays a critical role in lysosomal function and calcium signaling within cells.
Purpose of the Study:
- To investigate the function of the TRPML1 homolog in Drosophila melanogaster.
- To elucidate the relationship between TRPML1, autophagy, and TORC1 signaling.
- To explore potential therapeutic strategies for MLIV.
Main Methods:
- Generated Drosophila melanogaster mutants lacking the TRPML1 homolog.
- Assessed autophagy, lysosomal fusion, vesicle volume, and luminal Ca(2+) levels.
- Analyzed TORC1 signaling pathway activity.
- Investigated the effects of genetic TORC1 activation and dietary interventions (high-protein diet, rapamycin).
Main Results:
- Flies lacking TRPML1 exhibited incomplete autophagy, reduced pupal viability, and impaired amphisome-lysosome fusion.
- Mutant cells showed enlarged vesicles with higher luminal Ca(2+), decreased TORC1 signaling, and upregulated autophagy induction.
- Genetic activation of TORC1 or a high-protein diet rescued these defects, including pupal lethality and vesicle abnormalities.
- TORC1 activity reciprocally controlled TRPML1 function, with a high-protein diet promoting TRPML1 cortical localization, an effect blocked by rapamycin.
Conclusions:
- TRPML1 is essential for proper autophagy and lysosomal function, interacting with the TORC1 pathway.
- Modulating TORC1 signaling, potentially through dietary interventions like a high-protein diet, may offer a therapeutic approach to mitigate MLIV severity.
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